Abstract 24P
Background
Mutations (single nucleotide variants), deletions, and insertions in the kinase domain of EGFR gene are oncogenic drivers in NSCLC. These alterations can co-occur with one another (compound mutations) or exist as single mutations. The compound vs single mutation frequencies for classical and EGFR P-loop and αC-helix compressing (PACC) mutations have not been characterized and the impact of compound mutations on treatment outcomes are not understood.
Methods
Guardant Health liquid biopsy database was queried for NSCLC samples for their genetic profiling. Incidences EGFR mutations as single and compound mutations (excluding T790M and C797S) were analyzed and compared. A systematic literature search was performed and analyzed for esponse to different TKIs.
Results
Of the 104,393 lung cancer samples queried, 32,700 had an EGFR SNV/indel, of which, 17,488 (16.8%) had at least one SNV/indel within the kinase domain. The most frequent mutations were ex19del (6,670, 38.1%), L858R (4,700, 26.9%), G719 (712, 4.1%), S768 (335, 1.9%), and G709 (207, 1.2%). Classical EGFR mutations occur more frequently as a single mutation, each at 89.6% (5,970/6,665) and 76.7% (3,606/4,700) respectively. In comparison, PACC mutations occur more frequently as compound mutations (Table), G719 at 73.2% (521/712), S768 at 86.9% (291/335) and G709 at 97.1% (201/207). The most frequent compound mutation with G719 is G709 and S768, with S768 is V769, and with G709 is G719. A total of 852 cases with clinical response to EGFR TKIs from a clinical cohort were identified and analyzed by PACC mutation single (693) vs compound (159) (Table). As expected, PACC mutations responded better to 2nd-generation TKIs than 1st- or 3rd-generation TKIs. Compound mutations responded better than single mutations for each PACC mutation. Table: 24P
| PACC mutations | Guardant360 | Retrospective clinical response data | |||||||
| Case # | Percent | First-gen TKI | Second-gen TKI | Third-gen TKI | |||||
| ORR | N | ORR | N | ORR | N | ||||
| G719 | Single | 191 | 26.8% | 39% | 310 | 56% | 248 | 33% | 36 |
| Compound | 521 | 73.2% | 42% | 52 | 77% | 77 | 59% | 27 | |
| S768 | Single | 44 | 13.1% | 31% | 29 | 48% | 46 | 33% | 9 |
| Compound | 291 | 86.9% | 54% | 11 | 63% | 52 | 59% | 17 | |
| G709 | Single | 6 | 2.9% | 0% | 5 | 50% | 6 | 50% | 4 |
| Compound | 201 | 97.1% | 43% | 7 | 62% | 16 | 83% | 6 |
Conclusions
Compared to classical EGFR mutations, PACC mutations frequently occur as compound mutations, and tend to have improved response to EGFR TKIs than single PACC mutations.
Legal entity responsible for the study
The authors.
Funding
Has not received any funding
Disclosure
X. Le: Financial Interests, Personal, Advisory Board: AstraZeneca, Merck KGaA, Spectrum Pharmaceutics, Novartis, Boehringer Ingelheim, Eli Lilly, Hengrui, Janssen, Blueprint, Daiichi Sankyo, Regeneron, ArriVent, Abion, Pinetree therapeutics, AbbVie; Financial Interests, Institutional, Invited Speaker: Eli Lilly, EMD Serono, Regeneron, Janssen; Financial Interests, Institutional, Research Grant: Arrivent; Financial Interests, Institutional, Funding: Teligene. M. Stamboulian: Financial Interests, Personal, Full or part-time Employment: Guardant Health. S. Heeke: Financial Interests, Personal, Invited Speaker: AstraZeneca, Guardant Health; Financial Interests, Personal, Research Grant: Thermo Fisher. C. Lewis: Financial Interests, Personal, Full or part-time Employment: Guardant Health. L. Drusbosky: Financial Interests, Personal, Full or part-time Employment: Guardant Health. J. Heymach: Financial Interests, Personal, Advisory Board: Genentech, Mirati Therapeutics, Eli Lilly & Co., Janssen Pharmaceuticals, Boehringer Ingelheim Pharmaceuticals, Regeneron, Takeda Pharmaceuticals, BerGenBio, Jazz Pharmaceuticals, Curio Science, Novartis, AstraZeneca, BioAlta, Sanofi, Spectrum Pharmaceuticals, GSK; Financial Interests, Personal, Full or part-time Employment: MD Anderson Cancer Center; Financial Interests, Personal, Invited Speaker: Spectrum; Financial Interests, Institutional, Other, International PI for clinical trials: AstraZeneca; Financial Interests, Institutional, Other, International PI for two clinical trials: Boehringer Ingelheim; Financial Interests, Personal and Institutional, Other, Developed a drug: Spectrum; Financial Interests, Institutional, Invited Speaker: Takeda. A. Addeo: Financial Interests, Institutional, Advisory Board: BMS, AZD, Roche, Eli Lilly; Financial Interests, Personal, Advisory Board: Pfizer, Takaeda, MSD; Financial Interests, Institutional, Invited Speaker: Novartis. All other authors have declared no conflicts of interest.